The pathophysiology of ethanol-associated fetal injury is not fully understood. Ethanol is toxic to both somatic and brain development in the fetus. Ethanol may be directly neurotoxic. Intrauterine ethanol exposure may also be indirectly toxic to the fetus. We suggest that intrauterine ethanol exposure causes an elevation of fetal blood levels of the potentially neurotoxic amino acid, glutamate. The extracellular environment in the central nervous system (CNS) is normally low in amino acids. Excess extracellular glutamate is neurotoxic. An increase in excitotoxic amino acids such as glutamate could be detrimental to brain development. In utero ethanol is known to increase fetal brain glutamate concentrations. The blood brain barrier is incomplete in the fetus, so an elevation in serum glutamate would be one route for an increase in CNS glutamate levels. Preliminary data indicate that in utero ethanol exposure increases fetal serum glutamate levels in humans and experimental animals. Since the placenta is the critical interface for clearance of glutamate, it is likely that ethanol induced placental toxicity is central the alteration in fetal blood glutamate. Preliminary data with cultured human trophoblasts support this concept. We propose exploratory studies to evaluate the effect of intrauterine ethanol exposure on fetal glutamate homeostasis, with emphasis on placental glutamate clearance. Studies in both rats and humans will assess the effect of ethanol on fetal serum glutamate. Ethanol induced inhibition of placental clearance of fetal glutamate could be due to inhibition of uptake or metabolism. Accordingly, placental uptake of glutamate will be assessed in basal membrane vesicles prepared from rat placentas and from alcoholic human placentas exposed to ethanol in vivo. In addition, cultured human placental trophoblasts will be used to determine the effect of "chronic" in vitro ethanol exposure. Finally, glutamate metabolizing enzyme activities will be determined in placentas obtained from alcohol users and in cultured normal trophoblasts exposed to ethanol in vitro. The findings will have direct implications for understanding the pathophysiologic mechanisms of ethanol-associated fetal injury, particularly in the CNS. As an exploratory proposal, the findings should provide an impetus for future, more intensive research on the interrelationship between intrauterine ethanol exposure, fetal glutamate homeostasis and fetal brain injury.